CA2649265A1 - Microparticulate pharmaceutical forms resistant to immediate release of the active principle in the presence of alcohol - Google Patents

Abstract

The invention aims at minimizing the risks of release of the dose associated with the concurrent consumption of alcohol and certain pharmaceutical or dietary forms with modified release. The invention concerns an oral form comprising reservoir-type microparticles, with modified release of at least one active principle. The invention is characterized in that it is resistant to the immediate release of the dose of active principle in the presence of alcohol. In particular, the inventive oral form is characterized in that the releasing time of 50% of the active principle, in an alcohol-containing solution is not reduced by more than 3 times compared to the releasing time of 50% of the active principle in an alcohol-free aqueous medium. The form comprises an agent D which is a pharmaceutically acceptable compound of which the hydrating or solvating speed and capacity is higher in an alcohol-free aqueous medium than in an alcohol-containing solution.

Description

WO 2007/09364

2 PCT / EP2007 / 051528 MULTIMICROPARTICULAR PHARMACEUTICAL FORMS THAT RESIST
IMMEDIATE DISCHARGE OF THE ACTIVE INGREDIENT IN THE PRESENCE OF ALCOHOL
FIELD OF THE INVENTION
The field of the present invention is that of pharmaceutical forms or modified release dietetic drugs (PA) intended for oral administration.
The present invention relates to forms for the oral administration, containing at least one AP, and capable of maintaining a modified release of the PA in a alcoholic solution, that is to say not subject to a discharge of the dose in presence of alcohol.
Preferably the invention relates to pharmaceutical dosage forms modified the release profile is not significantly affected in solution alcoholic.
The present invention relates more particularly to the forms of the type referred to at preceding paragraph and comprising a plurality of microparticles tanks.
The present invention relates even more particularly to the forms pharmaceuticals for which the ingestion of alcohol during administration is not recommended.
The invention also relates to a method for preparing the forms pharmaceutical products defined above.
BACKGROUND OF THE INVENTION

The interest of modified-release dosage forms for administration of a medicine is well known. In particular, they allow better ensure the coverage of the therapeutic need because the plasma concentration PA can be maintained longer than in the case of instantaneous release forms.
In addition they avoid, or limit, the size and number of peaks concentration excessive plasma levels of PA, which decreases the toxicity of the drug and its effects secondary. Moreover, these systems allow, by their duration of action increased, to limit the number of daily doses, which reduces the stress for the patient and improves adherence to treatment Thus, systems have been sought to prolong the action of a drug, and there are many references to this goal. We will consult at this Regarding the work of Buri, Puisieux, Doelker and Benoît: Pharmaceutical Forms New, Lavoisier 1985, p. 175-227.
Modified Release Forms (MRs) have been summer developed, in particular for PAs with a narrow therapeutic window, that is to say, of which the effective doses are close to those that can be manifested effects to peak plasma peak (Cmax), the objective being to maintain prolonged plasma concentrations and remain below values where undesirable effects are to be feared.
Such forms have also been developed to allow impregnation of the organism in PA more stable and continuous, without the subject needing to multiply taken. There are thus forms containing, in a catch unit, the amount of PA
necessary for 24 hours of treatment, this form being of course intended to be administered only once a day.
Among the modified-release dosage forms can be distinguished systems where the release of PA is controlled by a coating surrounding the PA, these systems are also referred to as reservoir systems. In another group, that of matrix systems, the PA, intimately dispersed in a matrix, for example made of polymer, is released from the tablet by diffusion and erosion.
Much work has been done to ensure that the release of the PA
is effectively controlled, in order to avoid the massive overdose that would result of a liberation accidentally immediate the amount of PA scheduled for release extended. This control is extremely important in practice, since these are the most often active products with narrow therapeutic windows that benefit from the release technique changed. In this case, this accidental immediate release (dumping in English, literally 'dose dump') would have exactly the opposite effects to those whom the technical implementation was striving to achieve.
A discharge of the dose can occur for example in the case of a tablet monolithic matrix that the patient would chew before swallowing, short running a stage slow disintegration in the stomach. An advantageous way to avoid the risk linked to the chewing is to prepare a microparticulate form, each microparticle possessing the modified release properties.
The use of multi (micro) particulate forms limits the risk of massive liberation, and reduces the inter- and intra-individual variability associated with gastric emptying.
PCT application WO-A-96/11675 discloses modified release microcapsules for the oral administration of medicinal and / or nutritional active principles (PA), whose size is less than or equal to 1000 m. These microcapsules are constituted by particles coated with a coating material consisting of a mixture of a polymer forming (ethylcellulose), a hydrophobic plasticizer (castor oil), a surfactant or lubricant (magnesium stearate) and a nitrogen polymer (polyvinylpyrrolidone: povidone, PVP). These microcapsules are also characterized by their ability to stay a long time (at least 5 h) in the small intestine and to allow, during this stay, the absorption of PA on a longer than the natural transit time in the small intestine.

-3-PCT application WO-A-03/030878 discloses an oral pharmaceutical form multimicrocapsular in which the release of AP is governed by a double mechanism of triggering the release: "triggering time" and "triggering pH". This form is consisting of microcapsules (200 to 600 m) comprising a core containing the PA
to be covered a coating (maximum 40% by weight), the latter comprising a polymer A
hydrophilic carrier of ionized functions at neutral pH (Eudragit L) and a compound B
hydrophobic (wax with a melting point of 40-90 ° C), with B / A included between 0.2 and 1.5.
The coating of the microcapsules may comprise, in addition to the constituents essentials A and B, other conventional ingredients, such as:
dyes;
plasticizers, for example dibutyl sebacate;
hydrophilic compounds such as, for example, cellulose and its derivatives or polyvinylpyrrolidone and its derivatives;
- and their mixtures.
These examples illustrate the efforts undertaken to avoid a failure of different systems with modified release of (or) PAs.
Despite these efforts, however, it has recently emerged that fast of the mass of AP may occur during concomitant ingestion of form pharmaceutical MR and alcohol.
So in the US in October 2005, the Food and Drug Administration issued the idea that a study of the resistance of the MR forms to a discharge of the dose potentially alcohol-induced dumping should be carried out in order to some drugs.
Indeed, recent studies have shown that the presence of alcohol can accelerate release of an AP contained in a pharmaceutical form MR. This effect of alcohol can, in first analysis, to be explained by an alteration of the release system modified or by a modification of the solubility of the PA in the presence of a significant amount alcohol. This situation is all the more likely to meet - and the consequences are likely to be all the more cumbersome - that the amount of alcoholic beverages ingested is important, that the degree alcohol is high and the subject is fasting. Indeed in this last case, the stomach will contain essentially the ingested drink mixed with a small amount of Gastric acid.
So, in practice, the ingestion of alcohol along with the administration of a form pharmaceutical MR can lead to accelerated release and potentially dangerous PA in the patient. Depending on the type of AP, this accelerated release PA, at better, makes the pharmaceutical form MR completely ineffective, and at worst, compromises patient's vital prognosis.
This harmful acceleration of the release can lead to a loss of activity This will be the case, for example, with proton pump inhibitors.
whose

-4-too early release in acidic gastric medium will lead to their degradation, and therefore to ineffectiveness of the treatment.
Conversely, more formidable is the case of some tranquilizers, antidepressants or that of opioid analgesics, where it is the prognosis that will be at stake in because of the severity of side effects following an overdose.
A particular set of drugs for which a massive release of PA would be particularly harmful is that of the products for which it exists a adverse pharmacological interaction with alcohol, incompatibility, or a reinforcement of side effects:
- for example, drugs in the group of opioid analgesics have as undesirable effect of being able to induce respiratory depression; this one may be aggravated by the concomitant intake of alcohol due to false roads and of the swallowing pneumonia typically caused by alcohol abuse;
- also very used drugs like tranquilizers and - antidepressants have effects on the central nervous system (loss of vigilance, risk of drowsiness) which are accentuated by the simultaneous intake of alcohol;
- we can also mention the interactions of alcohol with antihistamines (potentiation of the sedative effect, drowsiness and loss of attention, dizziness), and - nonsteroidal anti-inflammatory drugs or NSAIDs (potentiation of risk of digestive bleeding).
In the case of monolithic matrix forms, the accidental discharge of the dose leads to very high levels of BP at the gastrointestinal level where find her shape, which can determine lesions.
The problem of discharge of the dose in the presence of alcohol has not been solved of satisfactorily so far, particularly in the case of the forms multimicroparticulate. In particular, there is a need for a form pharmaceutical modified-release multimicroparticles for PA administration by oral, able to maintain the modified release of AP in a solution alcoholic, that is to say whose release profile of the AP is not accelerated at the risk of engaging the life threatening of a patient, and preferably, whose PA release profile is not assigned significantly in alcoholic solution.

OBJECTIVES OF THE INVENTION

An essential objective of the present invention is to propose a form multimicroparticulate pharmaceutical composition with modified release of at least one active ingredient medicinal or dietary (PA), intended for oral administration, allowing to avoid or limit a discharge of the dose (dumping dose in English) induced by the

-5-alcohol consumption when administering this dosage form, what ensures greater therapeutic safety and better efficiency.
Another essential objective of the present invention is to propose a form multimicroparticulate pharmaceutical composition with modified release of at least one AP, destined to oral administration, for which the release of AP is not significantly affected by the presence of alcohol.
The microparticles according to the invention are possibly capable of being updates in the form of tablets, sachets, capsules, oral suspensions, etc.
Another essential objective of the present invention is to propose a form multimicroparticulate pharmaceutical composition with modified release of at least one AP, destined to oral administration, for which the release profile in of PA in the conventionally used and ethanol-free dissolution media is Similar to the profile obtained in these same media to which ethanol was added.
Another essential objective of the present invention is to propose a form multimicroparticulate pharmaceutical composition with modified release of at least one AP, destined to oral administration, with an in vitro release profile in the presence ethanol, which profile is not life-threatening for a patient.
Another essential objective of the present invention is to provide a form multimicroparticulate pharmaceutical composition with modified release of at least one AP, destined to oral administration, improved compared to those described in requests WO-A-96/11675 and WO-A-03/03878, in particular with regard to the behavior in alcoholic solution.
Another essential objective of the present invention is to propose a process for obtaining a release multimicroparticulate pharmaceutical form modified from to minus one PA, intended for oral administration and whose profile is release of PA
in vitro is not significantly affected in alcoholic solution, or at least the release is not accelerated at the risk of causing the vital prognosis of patient.
Definitions In the context of the present disclosure of the invention:
the abbreviation PA denotes both a single active principle and a mixture to several active subtances. PA can be in free form or in salt form, ester, hydrate, solvate, polymorph, isomers or other pharmaceutically acceptable forms acceptable;
- the ingested alcohol can come from different drinks or beverages alcoholic such as beer, wine, cocktails, spirits or mixtures thereof;
in vitro, the term alcohol represents ethanol and the terms solution alcoholic or alcoholic medium represents an aqueous solution of ethanol;
the term hypromellose represents hydroxypropylmethylcellulose or HPMC
;

-6-reservoir microparticles means microparticles comprising PA
and individually coated with at least one coating allowing the release modified AP;
- microparticle means indifferently microparticles reservoir and / or microparticles comprising PA not necessarily coated;
the dissolution profiles in vitro are carried out according to the indications of pharmacopoeia (5th edition, 2.9.3), where the classical dissolution media used are described. To simulate the gastric environment of a subject who has absorbed a strong quantity of alcohol, the dissolution medium is modified by addition of ethanol (qs 20% to 40% in vo lume);
- the abbreviation MR stands for: modified release;
- the term modified release means that the release of PA in vitro is such that 75% of the AP is released in a time greater than 0.75 h and, preferably, greater than 1 hour, and more preferably greater than 1.5 h. A pharmaceutical form to modified release may, for example, include an immediate release phase and a release slow. The modified release may be in particular a prolonged release and / or delayed.
Modified release dosage forms are well known in this art.
domain;
see for example Remington: The Science and Practice of Pharmacy, 19th edition, Mack publishing Co. Pennsylvania, USA;
- immediate release means that the release is not of type modified release and refers to the release by an immediate-release form of the most much of the PA
in a relatively short time, for example at least 75% of the AP are released in 0.75 h, from preferably in 30 min;
the multimicroparticulate oral pharmaceutical forms according to the invention are consisting of many microparticles smaller in size than millimeter. The The microparticle diameters discussed in this paper are, except contrary indication, average diameters by volume. These forms multimicroparticulate can be transformed into monolithic oral pharmaceutical forms as tablets, capsules, sachets, suspensions for reconstitution;
- the similarity between two dissolution profiles is evaluated using the similarity factor f2 as defined in the document "Quality of release products modified "from European Agency for the Evaluation of Medicinal Products, document referenced CPMP / QWP / 604/96 (Annex 3). A value of f2 between 50 and 100 indicates that two dissolution profiles are similar;
- by discharge of the dose (dumping dose) means a release immediate and no desired dose after oral ingestion.

-7-BRIEF DESCRIPTION OF THE INVENTION

It is to the merit of the inventors to have found a formulation which makes it possible delete or decrease the changes in the PA release profiles observed in alcoholic solution.
The present inventors have developed MR dosage forms having a resistance to a dose discharge induced by alcohol. This property advantageous can in particular to be demonstrated under conditions reproducing the characteristics physicochemicals expected in vivo. Periodic alcoholism or "binge drinking "form of alcoholism characterized by high consumption access, typically in end of week, alternating with long periods of abstinence or moderation, is become in some circles an increasingly widespread social activity. And parallel has increased the risk of accidental release of the PA dose contained in a form Pharmaceutical MR in a subject who also reportedly ingested a large amount alcohol.
The inventors have carried out studies of the sensitivity of various forms pharmaceutical MR in the presence of alcohol. The approach chosen for measure the resistance of pharmaceutical forms MR to a dose-induced discharge of the alcohol consists in modifying the classical tests of dissolution of the forms pharmaceutical MR in introducing ethanol into the dissolution medium, for example at a concentration of 20% or 40% (v / v). The order of magnitude of the final volume is 50 to 900 mL.
For a number of pharmaceutical forms MR, it is observed that administration of said form with alcoholic beverages would lead to a acceleration unwanted release of the AP. To solve this problem, the present invention relates to a new multimicroparticulate pharmaceutical form to release modified form of at least one medicinal PA for administration by oral, characterized in that it is able to maintain the modified release of the PA in a alcoholic solution, and preferably in that the release profile is not affected significantly in alcoholic solution.
More specifically, the present invention relates to an oral pharmaceutical form comprising reservoir-type microparticles with modified release from minus one PA, this form resistant to the immediate discharge of the dose of PA in the presence alcohol.
Preferably, the oral pharmaceutical form according to the invention, which comprises of the modified-release reservoir-type microparticles of at least one PA also well in aqueous dissolution media than in alcoholic solutions, is characterized in that that the release time of 50% of PA in alcoholic solution:
- is not decreased by more than 3 times compared to the release time of 50 % of PA
measured in an aqueous medium free of alcohol;

-8-- preferably is not decreased by more than 2 times in relation to the time of release of 50% of the PA measured in an aqueous medium free of alcohol;
- preferably is not decreased by more than 1.5 times compared to the time of release of 50% of the PA measured in an aqueous medium free of alcohol;
- is preferably similar to that measured in aqueous medium, according to the factor of similarity f2 defined above;
- even the release time of 50% of the PA in alcoholic solution is greater than release time of 50% PA in aqueous medium free of alcohol.

This pharmaceutical form according to the invention comprises microparticles of type reservoir and at least one agent D, which is a pharmaceutically active compound acceptable and whose speed or ability to hydrate or solvate is greater in aqueous medium alcohol-free only in alcoholic solution. The reservoir microparticles have, preferably, an average diameter of less than 2000 m, more preferably between 50 and 800 m, and more preferably between 100 and 600 m. In In addition, microparticles reservoirs are individually constituted by a heart including PA
and coated with a coating comprising:
at least one polymer A that is insoluble in the liquids of the digestive tract;
at least one plasticizing agent B;
- optionally at least one surfactant C.
BRIEF DESCRIPTION OF THE FIGURES

Figure 1 Schematic representation of the structure of a microparticle coated.
Figure 2 Schematic representation of the structure of a microparticle coated.
Figure 3 Schematic representation of the structure of a pellet or granule comprising microparticles and agent D as binder.
Figure 4: Schematic representation of a coated tablet containing microparticles.
Figure 5 Schematic representation of a capsule coated with a coating based agent D, the capsule containing microparticles.
Figure 6 Dissolution of aciclovir capsules prepared as example 1.
Figure 7 Dissolution of the metformin capsules prepared in Example 2.
Figure 8 Dissolution of aciclovir capsules prepared as example 3.
Figure 9 Dissolution of metformin capsules prepared in Example 4.
Figure 10: Behavior of starch sodium glycolate (Primojel (k / Avebe) in water (Fig. 10A) and in an alcoholic solution (Fig. 1 OB) after 15 min of contact.
Figure 11: Behavior of guar gum (Grindsted Guar / Danisco) in the water (Fig. 11 A) and in an alcoholic solution (Fig. 11B) after 15 minutes of contact.

-9 Figure 12: Behavior of hydroxypropyl methylcellulose (Methocel (k E5 /
Dow) in water (Fig. 12A) and in an alcoholic solution (Fig. 12B) after 30 minutes contact.
Figure 13: Dissolution of metformin capsules prepared in Example 6.

DETAILED DESCRIPTION OF THE INVENTION

The oral pharmaceutical or dietetic form according to the invention comprises tank-type microparticles and allows the modified release of the PA also well in the aqueous dissolution media only in alcoholic solutions. This shape according to the invention is multimicroparticular, that is to say that it comprises between other microparticles tanks with a core comprising coated or film-coated PA
by a coating. This PA heart, or PA microparticle, can be:
raw (pure) PA in pulverulent form, and / or a matrix granule of PA mixed with various other ingredients, and / or a supported granule, such as a neutral support, for example cellulose or in sugar, covered with at least one layer comprising PA.
In the case of a matrix granulate, the matrix contains the PA and possibly others pharmaceutically acceptable excipients, such as binding agents, surfactants, disintegrants, fillers, agents controlling or modifying the pH
(Buffer).
In the case of a supported granulate, the neutral support may be composed of sucrose and / or dextrose and / or lactose, and / or mixture sucrose / starch. The neutral carrier can also be a cellulose microsphere or any other particle of a pharmaceutically acceptable excipient. Advantageously, the neutral support has a average diameter between 1 and 800 m and preferably between 20 and 500 m.
The active layer may optionally comprise, in addition to the PA, one or many pharmaceutically acceptable excipients, such as binding agents, surfactants, disintegrants, fillers, agents controlling or modifying the pH
(Buffer).
The form according to the invention may comprise microparticles of PA other than reservoir microparticles. It could be, for example, microparticles to immediate release of PA. These last ones can be for example microparticles of PA uncoated, of the same type as those used in the preparation of microparticles tanks according to the invention, and comprising one or more PA.
In addition, all the microparticles (microparticles reservoirs and / or uncoated microparticles) constituting the form according to the invention can be made of different populations of microparticles, these populations differing between they at least by the nature of the PA (s) contained in these microparticles and / or by composition of the coating and / or the thickness of the coating.

-10-According to a first embodiment, at least a part of the microparticles to modified release of AP each comprises a PA-coated microparticle by to minus a coating allowing the modified release of the AP.
Preferably, the microparticle of PA is a granulate comprising the (the) AP
and one or a plurality of pharmaceutically acceptable excipients.
According to a second embodiment, at least a part of the microparticles to modified release of PA each comprises a neutral support, at least one active layer comprising the PA (s) and coating the neutral support, and at least one coating allowing the modified release of the AP.
As recalled above, the microparticles reservoirs are individually constituted by a core comprising the PA and coated with a coating.
The coating governs the modified release of the AP. He understands :
at least one polymer A that is insoluble in the liquids of the digestive tract;
at least one plasticizing agent B;
- optionally at least one surfactant C.
The coating of the reservoir microparticles contains an insoluble polymer A
in digestive tract liquids at 70% to 95%, preferably 75% to 95%, and more preferentially still, from 80% to 95% of the mass of the coating without agent D. The polymer A is preferably selected from the following group of products the non-water-soluble derivatives of cellulose, - (meth) acrylic (co) polymer derivatives, - and their mixtures.
More preferably, the polymer A is selected from the group of products the following: ethylcellulose, cellulose acetate butyrate, cellulose, ammonio-methacrylate copolymers type A and type B (Eudragit RS, Eudragit RL, Eudragit RS PO, Eudragit PL PO), esters of poly (meth) acrylic acids (Eudragit NE 30D) and mixtures thereof; ethylcellulose and / or cellulose acetate being particularly preferred.
The plasticizing agent B is present in the coating of the microparticles tanks to 1% to 30% w / w, preferably 2% to 25% w / w, and more preferably still, from 5% to 20% by weight of the coating without agent D. The plasticizing agent B is selected in the following product group:
glycerol and its esters, preferably in the following subgroup:
acetylated glycerides, glyceryl mono-stearate, glyceryl triacetate, glyceryl tributrate, phthalates, preferably in the following subgroup: dibutyl phthalate, diethylphthalate, dimethylphthalate, dioctyl phthalate, citrates, preferably in the following subgroup:
acetyltributylcitrate, acetyltriethylcitrate, tributylcitrate, triethylcitrate,

-11-the sebacates, preferably in the following subgroup: diethyl sebacate, dibutyl, - adipates, azelates - benzoates, chlorobutanol, polyethylene glycols, - vegetable oils, fumarates, preferably diethylfumarate, malates, preferably diethyl malate, oxalates, preferably diethyloxalate, succinates; preferably the dibutylsuccinate, - butyrates, esters of cetyl alcohol, malonates, preferably diethyl malonate, castor oil (the latter being particularly preferred), - and their mixtures.
Surfactant C is present in the coating of microparticles tanks to 0 to 30% w / w, preferably 0 to 20% w / w, and more preferentially, from 5 to 15% of the weight of the coating without agent D. The surfactant C is preference selected in the following product group:
the alkaline or alkaline earth salts of fatty acids, sodium dodecyl sulphate and sodium docusate being preferred, polyoxyethylenated oils, preferably hydrogenated castor oil polyoxyethylene, polyoxyethylene-polyoxypropylene copolymers, polyoxyethylenesorbitan esters, polyoxyethylenated castor oil derivatives, stearates, preferably of calcium, magnesium, aluminum or zinc, polysorbates, stearyl fumarates, preferably sodium, - the glycerol behenate, - benzalkonium chloride acetyltrimethylammonium bromide, - and their mixtures.
The mono- or multilayer coating may comprise various other adjuvants additives conventionally used in the field of coating. he can be, by for example, pigments, dyes, fillers, defoamers, etc.

-12-According to a particular embodiment of the invention, the coating governing the modified release of the AP by the microparticles reservoirs is constituted one layer or a single coating film. This simplifies their preparation and limit the coating rate.
Advantageously, the coating has sufficient mechanical strength to avoid tearing and / or bursting in the body until the end of release of the AP. This ability of the coating to maintain its integrity physical same after complete elution of PA is observed especially for thicknesses coating between 2 m and 100 m, ie coating rates (coating mass outside agent D
on total mass of the microparticle) between 3 and 85%.
It's important to note that the alcohol resistance feature is only not acquired at the expense of other specifications required for a particular form Pharmaceutical modified release. In particular, the pharmaceutical form according to the invention may be suitable for a large number of PAs with solubilities in very varied, for example between a few hundredths of a milligram per liter and a few hundreds of grams per liter.
Moreover, the pharmaceutical form according to the invention makes it possible to adjust the release the PA over a very wide range of times, for example between 1 and 30 preferences between 2 am and 4 pm It is within the abilities of those skilled in the art to adjust time to liberation by varying in particular the composition and / or the thickness of coating, and / or the average size of the microparticles.

Agent D is a pharmaceutically acceptable compound whose rate or ability to hydrate or to solvate is superior in aqueous medium free of alcohol alcoholic solution. It could be :
a compound with a higher solubilization rate in water than in solution alcoholic;
a compound that is soluble in water and insoluble in alcoholic solution; or - a compound, insoluble in water or alcoholic solution, which swells more, or more quickly, in water as in alcoholic solution.
Preferably, the agent D is chosen from the following group of products:
crosslinked carboxyalkylcelluloses: carboxymethylcelluloses crosslinked (e.g.
croscarmellose sodium), - polyalkylene oxides (eg polyethylene oxide or polypropylene oxide), - (hydroxy) (alkyl) celluloses (eg hydroxypropylcellulose, hypromellose [or HPMC]), carboxyalkylcelluloses (eg carboxymethylcellulose) and their salts, celluloses (powder or microcrystalline), potassium polacrilin, polysaccharides, for example:

-13-= native starches (eg maize, wheat or potato) or modified (by ex.
with sodium glycolate), alginates and their salts, such as sodium alginate, = guar gums, = carrageenans, = pullulans, = the pectins, = chitosans and their derivatives, = and their mixtures, proteins, for example:
= gelatin, = albumins, = casein, = lactoglobulins, = and their mixtures, clays such as bentonite, laponite, - and their mixtures.
Even more preferably, agent D is selected from the group of products following:
hydroxyalkylcelluloses (eg hydroxypropylcellulose, hypromellose [or HPMC]
- guar gums, - carrageenans, - pullulans, - and their mixtures.
Agent D can be incorporated in different ways, possibly combined enter they, in the pharmaceutical form according to the invention. He can be :
one of the constituents of the PA core (or microparticle not coated with PA), is :
= in the neutral support of microparticles and / or = in the layer containing PA, deposited on the neutral support of microparticles and / or in the granule containing the PA; and or one of the constituents of the coating of the microparticles; and or - in mixture with the microparticles; and or - one of the outer constituents of a monolithic form (eg a capsule, coating a tablet or capsule).
According to a first embodiment of the invention, agent D is present in the heart PA, or microparticle uncoated PA. Preferably, agent D is present

-14-in the core of the microparticles at 5 to 70%, preferably 15%
at 60% of the total mass of the heart of PA.
According to a second embodiment of the invention, agent D is included in the coating of the microparticles. In this case, the agent D can constitute to him only one layer coating inside or outside the coating controlling the diffusion. he can also be mixed with the constituents A, B and optionally C of the coating which governs the release modified PA. Preferably, the agent D is present in the coating at a rate of from 3 to 30%, preferably from 10% to 20%, of the total mass of the coating. Preferably, we choose the following compounds: Polymer A is ethylcellulose, the agent plasticizer B is the oil of castor, the surfactant is polysorbate, and the agent D is selected from guar gum, hypromellose [or HPMC], sodium carboxymethylcellulose, pullulan, the starch glycolate, and mixtures thereof.
According to a third embodiment, the agent D is included in the phase binding of granules or pellets or tablets including microparticles.
The granules, pellets or tablets are obtained by the techniques known to man of art as for example granulation, extrusion or compression. Agent D is present in mixture with the microparticles at 2 to 30% w / w, preferably 5 to % to 25%
p / p, and more preferably still 5% to 20% w / w, of the total mass of the mixed.
According to a fourth embodiment, the agent D is one of the components of the material constituting the capsule that contains the microparticles. For example, the capsule is present in the form of a capsule based on an agent D, preferably based on pullulane, of hypromellose [or HPMC] or their mixture.
According to a fifth embodiment, the agent D is included in a coating deposited on the capsule containing the microparticles or on the tablet containing the microparticles. For example, the capsule is gelatin-based, and the coating contains sodium carboxymethylcellulose as agent D, preferably with 25%
p / p of sodium carboxymethylcellulose relative to the weight of the capsules empty.
In the case of the fourth and fifth modes, it will be possible to deposit on the capsule where the compressed a topcoat.
With respect to Agent D, the five embodiments can be combined between them ;
moreover it is possible to incorporate different agents D for each mode of realization.
Preferably the form according to the invention is constituted by one or more same galenic units (eg tablet, capsule or sachet) each containing the microparticles.
The form according to the invention can also be in the form of a multidose oral suspension, reconstituted from powder and water before administration.
The form according to the invention can also be in the form of a capsule containing a tablet, this tablet containing reservoir microparticles PA; the

-15-tablet may contain one or more D agents, and the capsule may be coated by one or several agents D.
Advantageously, the form containing the modified release microparticles of PA also comprises pharmaceutically acceptable excipients, classics, and useful for example to present the microparticles in tablet form.
These excipients may include:
compressors, such as microcrystalline cellulose or mannitol, - dyes, - disintegrators, flow agents such as talc, colloidal silica, lubricants such as, for example, glycerol behenate, stearates, - aromas, - curators, - and their mixtures.
The final pharmaceutical form, in tablet or capsule form, may be coated according to the techniques and formulas known to those skilled in the art for improve its presentation: color, appearance, taste masking, etc.
The new pharmaceutical forms based on PA according to the invention are original in their structure, presentation and composition and are manageable per os, especially in single daily doses.
It can be interesting to mix in the same capsule, the same tablet or a same powder for oral suspension, at least two types of microparticles to kinetics of release of the different AP, for example immediate release and modified release. he can also be interesting to mix two (or more) types of microparticles, containing each a different PA, released according to a release profile that is clean.
Thus, the present invention aims in particular at a pharmaceutical form multimicroparticular, characterized in that it contains a plurality of populations of microparticles, the said populations differing from each other at least by nature of PA
content and / or the composition of the coating and / or the thickness of coating and / or the location of agent D.
The present invention also relates to a pharmaceutical form multimicroparticles, comprising at least two types of microparticles with kinetics of release of the different AP, for example immediate release and modified release or still with modified release with different release kinetics.
The present invention also relates to a pharmaceutical form multimicroparticulate, further comprising a mixture of several PAs, each of them being contained in microparticles having identical release kinetics or different.

-16-Without wishing to be limiting, it must nevertheless be emphasized that the form pharmaceutical composition according to the invention is particularly interesting in that she can present as a single daily oral dose of 100 (one hundred) at 500,000 microparticles tanks containing PA.
Furthermore, the invention aims to use microparticles such as defined above for the preparation of multimicroparticulate oral forms, pharmaceuticals or dietary, preferably in the form of tablets, powder for oral suspension or capsules.
Finally, the invention also aims at an improved therapeutic treatment, consisting basically to administer a safer pharmaceutical form with regards to regards the risk of discharge of the dose (dose dumping) in the presence of alcohol.
According to another of its aspects, the invention also relates to microparticles per se as defined above.
The subject of the present invention is also the processes for obtaining the pharmaceutical forms according to the invention as defined above, said methods breaking down into several stages consisting essentially of:
a) preparing hearts (uncoated microparticles) of AP by:
extrusion / spheronization of PA with possibly one or more agent (s) From where pharmaceutically acceptable excipient (s), and / or;
wet granulation of PA with possibly one or more agent (s) D or pharmaceutically acceptable excipient (s), and / or;
- compaction of AP with possibly one or more agent (s) D or excipient (s) pharmaceutically acceptable, and / or;
PA sputtering, possibly with one or more agent (s) D or excipient (s) pharmaceutically acceptable, in dispersion or in solution in a solvent aqueous or organic on a neutral support or agent D particles, and / or;
sieving of powder or PA crystals;
b) prepare microparticles reservoirs of PA by - Spraying in a fluidized air bed of a solution or dispersion containing one or more compounds A, B and optionally one or more compounds C and / or D on the PA microparticles; the microparticles of PA may have been at pre-coated by one or more agents D; coated microparticles can eventually be coated with one or more agents D;
c) prepare the final form of the drug by:
granulation and / or extrusion / spheronization of microparticles PA with a agent D for setting in capsule or sachet; or - mixture of microparticles tank PA with possibly one or many agent (s) D and pharmaceutically acceptable excipients for obtaining a compressed ; this tablet may optionally be coated in a coating turbine by one or

-17-multiple layers containing Agent D and / or pharmaceutically excipients acceptable; or - Put in capsule of the microparticles tanks of PA; the capsules can possibly be embedded in a turbine or fluidised air bed by one or several agent (s) D
and / or pharmaceutically acceptable excipients; or packaging the microparticles of PA reservoirs with a possibly or several agent (s) D and / or pharmaceutically acceptable excipients; or tabletting tablets containing microparticles of PA reservoirs, the tablet containing one or more agents D and capsules that may be coated by one or several agents D.

These are interesting general methodologies that allow produce the forms of the invention in a simple and economical manner.
The invention can be implemented independently of the solubility of PA
in the water. Four classes of AP are defined according to their solubility, according to the US Food and Drug Administration's Biopharmaceutics Classification System (Starch GL et al. "A guideline for a biopharmaceutics drug classification:
the correlation of in vivo drug product dissolution and in vivo bioavailability ", Pharmaceutical Research, 1995, vol. 12: 413-420). PAs belonging to these different classes may to be used according to the present invention.
The AP contained in the coated microparticles according to the invention is advantageously chosen from at least one of the families of active substances following:
the agents of treatment of the alcohol abuse, the agents of treatment of the sickness Alzheimer's disease, anesthetics, acromegaly treatment agents, analgesics, antiasthmatics, allergy treatment agents, anticancer drugs, inflammatory agents, anticoagulants and antithrombotics, anti-inflammatory convulsants, antiepileptics, antidiabetics, antiemetics, antiglaucoma, the Antihistamines, anti-infectives, antiparkinsonians, anti-cholinergic antitussive agents, carbonic anhydrase inhibitors, agents cardiovascular:
lipid-lowering, anti-arrhythmic, vasodilatory, antianginal, anti-inflammatory, hypertensives, vasoprotective agents and cholinesterase inhibitors, the agents for the treatment of disorders of the central nervous system, stimulants of the central nervous system, contraceptives, fertility promoters, inducers and inhibitors of uterine labor, agents of treatment of cystic fibrosis, dopamine receptor agonists, agents of treatment of endometriosis, dysfunction treatment agents erectile, Fertility treatment agents, treatment agents disorders gastrointestinal;
immunomodulators and immunosuppressants, the treatment agents of disorders of memory, anti-migraine, muscle relaxants, nucleosides, the agents

-18-treatment of osteoporosis, parasympathomimetics, prostaglandins, agents psychotherapeutic: sedatives, hypnotics, tranquillizers, neuroleptics, anxiolytics, psychostimulants and antidepressants, dermatological treatment agents, steroids and hormones, amphetamines, anorectics, non-pain medications analgesics, antiepileptics, barbiturates, benzodiazepines, hypnotics, laxatives, psychotropics.
Agents for the treatment of alcohol abuse are, for example: chlorazepate, chlordiazepoxide, diazepam, disulfiram, hydroxyzine, naltrexone, and their salts, their esters, their hydrates, their polymorphs and their isomers.
Anesthetics are for example: lidocaine, midazolam, and their salts, their esters, their hydrates, their polymorphs and their isomers.
Examples of analgesics and / or anti-inflammatory agents are paracetamol, aspirin, buprenorphine, butorphanol, celecoxib, clofenadol, choline, clonidine, codeine, diclofenac, diflunisal, dihydrocodeine, dihydroergotamine, dihydromorphine, ethylmorphine, etodolac, eletriptan, eptazocine, ergotamine, fentanyl, fenoprofen, hyaluronic acid, hydrocodone hydromorphone, hylan, ibuprofen, indomethacin, ketorolac, ketotifen, levomethadone, levallorphane, levorphanol, lidocaine, mefenamic acid, meloxicam, meperidine, methadone, morphine, nabumetone, nefopam, naloxone, naltrexone, naproxen, naratriptan, nefazodone, mormethadone, oxapozine, oxycodone, oxymorphone, pentazocine, pethidine, phenpyramide, piritramide, piroxicam, propoxyphene, rizatriptan, ketoprofen, sulindac, sumatriptan, tebacone, tilidine, tolmetin, tramadol, zolmitriptan, and their salts, their esters, their hydrates, their polymorphs and their isomers.
Antiasthmatics are for example: ablukast, azelastine, bunaprolast, cinalukast, cromitrile, cromolyne, enofelast, isamboxole, ketotifen, levcromékaline, lodoxamide, montelukast, ontazolast, oxarbazole, oxatomide, piriprost potassium, pirolate, pobilukast, edamine, pranlukast, quazolast, repirinast, ritolukast, sulukast, tetrazolastmeglumine, tiaramide, tibenelast, tomelukast, tranilast, verlukast, vérofylline, zarirlukast, and their salts, esters, hydrates, polymorphs and their isomers.
Anticancer agents are for example: adriamycin, aldesleukin, allopurinol altretamine, amifostine, anastrozole, asparaginase, betamethasone, bexarotene, bicalutamide, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil cisplatin, cladribine, conjugated estrogen, cortisone, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, dactinomycin, denileukin, dexamethasone, discodermolide, docetaxel, doxorubicin, eloposidem, epirubicin, epoetin, epothilones, estramustine, esterified estrogen, ethinyl estradiol, etoposide, exemestane, flavopirdol, fluconazole, flurarabine, fluorouracil, flutamide, floxuridine, gemcitabine, hexamethylmelamine, hydrocortisone, hydroxyurea, ifosfamide, lemiposide, letrozole, leuprolide, levamisole, levothyroxine, lomustine, mechlorethamine, melphalan, mercaptopurine, megestrol

-19-methotrexate, methylprednisolone, methyltestosterone, mithramycin, mitomycin mitotane, mitoxantrone, mitozolomide, mutamycin, nilutamide, pamidronate, pentostatin, plicamycin, porfimer, prednisolone, procarbazine, semustine, streptozocin, tamoxifen, temozolamide, teniposide, testolactone, thioguanine, tomudex, toremifene, tretinoin semustine, streptozolocin, verteprofine, vinblastine, vincristine, vindesine, vinorelbine, and their salts, their esters, their hydrates, their polymorphs and their isomers.
Anticoagulants and antithrombotics are, for example: warfarin, danaparoid, alprostadil, anagralide, argatroban, ataprost, betaprost, camonagrel, cilostazol, clinprost, clopidogrel, cloricromen, dermatan, desirudin, domitroban, drotaverine, epoprostenol, fradafiban, gabexate, iloprost, isbogrel, lamifiban, lefradafiban, lepirudin, levosimendan, lexipafant, melagatran, nafagrel, nafamostat, nizofenone, orbifiban, ozagrel, pamicogrel, quinobendan, sarpogralate, satigrel, simendan, ticlopidine, vapiprost, tirofiban, xemilofiban, Y20811, and their salts, esters, hydrates, polymorphs and their isomers.
Anticonvulsants are, for example: carbamazepine, clonazepam, clorazepine, diazepam, divalproex, ethosuximide, ethotion, felbamate, fosphenytoin, gabapentin lamotrigine, levetiracetam, lorazepam, mephenytoin, mephobarbital, metharbital, methsuximide, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, tiagabine, topiramate, valproic acid, vigabatrin, zonisamide, and their salts, their esters, their hydrates, their polymorphs and their isomers.
Antidiabetic agents are, for example: acarbose, acetohexamide, carbutamide, chlorpropamide, epalrestat, glibomuride, gliclazide, glimepiride, glipizide, gliquidone, glisoxepide, glyburide, glyhexamide, metformin, miglitol, nateglinide, orlistat, phenbutamide, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide tolcyclamide, tolrestat, troglitazone, voglibose, and their salts, their esters, their hydrates, their polymorphs and their isomers.
Examples of antiemetic agents are: alprazolam, benzquinamide, benztropine, betahistine, chlorpromazine, dexamethasone, difenidol, dimenhydrinate, diphenhydramine, dolasetron, domperidone, dronabinol, droperidol, granisetron, haloperidol, lorazepam, meclizine, methylprednisolone, metoclopramide, ondansetron, perphenazine, prochlorperazine, promethazine, scopolamine, tributine, triethylperazine, triflupromazine, trimethobenzamide, tropisetron, and their salts, their esters, their hydrates, their polymorphs and their isomers.
Antiglaucoma agents are, for example: alprenoxime, dapiprazole, dipivefrin, latanoprost, naboctate, pimabine, and their salts, their esters, their hydrates, their polymorphs and their isomers.
Antihistamines or beta agonists are for example: acepromazine, acrivastine, activastine, albuterol, alimemazine, antazoline, azelastine, bitolterol,

-20-amlexanox, benzydamine, brompheniramine, cetirizine, chlorpheniramine, cimetidine cinnarizine, clemastine, clofedanol, cycloheptazine, cyproheptadine, difencloxazine, diphenhydramine, dotarizine, ephedrine, epinastine, epinephrine, ethylnorepinephrine, fenpentadiol, fenpotol, fexofenadine, flurbiprofen, hydroxyzine, isoetharine, isoproterenol, ketorolac, levocetirizine, levomepromazine, loratidine, mequitazine, metaproterenol, niaprazine, oxatomide, oxomemazine, phenylephrine, phenylpropanoamine, pirbuterol, promethazine, pseudoephedrine, pyrilamine, ranitidine salmeterol, terbutaline, terfenadine, tranilast, xanthine derivatives; and their salts, their esters, their hydrates, their polymorphs and their isomers.
Anti-infective agents, including antibiotics, antifungals, the antivirals, for example: abacavir, aciclovir, albendazole, amantadine, amphotericin, amikacin, aminosalicylic acid, amoxicillin, ampicillin, amprenavir, atovaquine, azithromycin, aztreonam, cefaclor, cefadroxil, cefazolin, cefdinir, cefixime, cefpodoxime proxetil, cefprozil, ceftibutene, cephalexin, chloroquine, cidofovir, cilastatin, ciprofloxacin, clarithromycin, clavulanic acid, clindamycin, dalfopristin, dapsone, delavirdine, demeclocycline, didanosine, doxycycline, efavirenz, enoxacin, erythromycin ethambutol, ethionamide, famciclovir, fluconazole, flucytocin, foscamet, ganciclovir gatifloxacin, griseofulvin, hydroxychloroquine, indinavir, isoniazid, itraconazole, ivermectil, ketoconazole, lamivudine, levofloxacin, linizolide, lomefloxacin, loracarbef, mebendazole, mefloquine, methanamine, metronidazole, minocycline, moxifloxacin, acid nalidixic, nelfinavir, neomycin, nevirapine, nitrofurantin, norfloxacin, ofloxacin, oseltamivir, oxytetracycline, penicillin V, pefloxacin, praziquantel, pyrazinamide pyrimethamine, quinidine, quinupristine, re-tonavir, ribavirin, rifabutin, rifampicin rimantadine, saquinavir, sparfloxacin, stavudine, streptomycin, sulfamethoxazole tetramycin, terbinafine, tetracycline, thiabendazole, tobramycin, trimethoprim, troleandomycin, trovafloxacin, valaciclovir, vancomycin, zalcitabine, zanamivir, zidovudine, and their salts, esters, hydrates, polymorphs and their isomers.
Antiparkinsonian drugs are for example: amantadine, adrogolide, altinicline, benzatropine, biperidene, brasofensine, bromocriptine, budipine, cabergoline, dihydrexidine, entacapone, etilevodopa, idazoxane, iometopane, lazabemide, melevodopa, carbidopa, levodopa, mofegiline, moxiraprine, pergolide, pramipexole, Quinelorane, rasagiline, ropinirole, seligiline, talipexole, tolcapone, trihexyphenidyl, and their salts, their esters, their hydrates, their polymorphs and their isomers.
Examples of antirheumatic agents are: azathioprine, betamethasone, celecoxib, cyclosporine, diclofenac, hydroxychloroquine, indomethacin, acid mercaptobutanedioic acid, methylprednisolone, naproxen, penicillamine, piroxicam, prednisolone, sulfasalazine, and their salts, esters, hydrates, their polymorphs and their isomers.

-21-Antiplatelet agents are, for example: anagrelide, aspirin, cilostazol clopidogrel, dipyridamole, epoprostenol, eptifibatide, ticlopidine, tinofiban, and their salts, their esters, their hydrates, their polymorphs and their isomers.
Antispasmodics and anticholinergics are for example: aspirin, atropine, diclofenac, hyoscyamine, mesoprostol, methocarbamol, phenobarbital, scopolamine, and their salts, esters, hydrates, polymorphs and their isomers.
Antitussives are for example: paracetamol, acrivastine, benzonatate, beractant, brompheniramine, caffeine, calfactant, carbetapentane, chlorpheniramine, codeine, colfuscerin, dextromethorphan, doxylamine, fexofenadine, guaphenesine, metaproterenol, montelukast, pentoxyphillin, phenylephrine, phenylpropanoamine, pirbuterol, pseudoephedrine, pyrilamine, terbutaline, theophylline, zafirlukast, zileuton and their salts, their esters, their hydrates, their polymorphs and their isomers.
Inhibitors of carbonic anhydrase are, for example: acetazolamide, dichlorphenamide, dorzolamide, methazolamide, sezolamide, and their salts, their esters, their hydrates, their polymorphs and their isomers.
Cardiovascular agents, including lipid-lowering drugs, anti-inflammatory agents, arrhythmic, vasodilators, antianginal drugs, antihypertensives, vasoprotective agents, are example: acebutolol, adenosine, amiodarone, amiloride, amlodipine, nitrate amyl atenolol, atorvastatin, benzepril, beiridil, betaxalol, bisoprolol, candesartan, captopril, cartenolol, carvedilol, cerivastatin, chlorthalidone, chlorthiazole, clofibrate, clonidine, colestipol, colosevelam, digoxin, diltiazem, disopyramide, dobutamine, dofetilide, doxazosin, enalapril, epoprostenol, eprosartan, esmolol, ethacrynate, erythrityl, felodipine, fenoidapam, fosinopril, flecainide, furosemide, fluvastatin, gemfibrozil, hydrochlorthiazide, hydroflumethazine, ibutilide, indapamide, isosorbide, irbesartan, labetolol, lacidipine, lisinopril, losartan, lovastatin, mecamylamine, metoprolol metarminol, metazolone, methylchlothiazide, methyldopa, metyrosine, mexiletine midrodine, milrinone, moexipril, nadolol, niacin, nicardipine, nicorandil, nifedipine, nimodipine, nisoldipine, nitroglycerin, phenoxybenzamine, perindopril, polythiazide, pravastatin, prazosin, procaininamide, propafenone, propranolol, quanfacin, quinapril, quinidine, ranipril, simvastatin, sotalol, spironolactone, telmisartan, terazosin, timolol, tocainamide, torsemid, trandolapril, triamterene, trapidil, valsartan, and their salts, their esters, their hydrates, their polymorphs and their isomers.
Vasodilators are, for example: adenosine, alverine, caffeine, dihydroergocomine, enalapril, enoximone, iloprost, kallone, lidoflazine, nicardipine, nimodipine, nicotinic acid, papaverine, pilocarpine, salbutamol, theophylline trandolapril, uradipil, vincamine, and their salts, esters, hydrates, their polymorphs and their isomers.

-22-Examples of cholinesterase inhibitors are donepezil, neostigmine, pyridostigmine, rivastigmine, tacrine, and their salts, esters, hydrates, their polymorphs and their isomers.
Stimulants of the central nervous system are for example: caffeine, doxapram, dexoamphetamine, donepezil, methamphetamine, methylphenidate, modafinil, neostigmine, pemoline, phentermine, pyridostigmine, rivastigmine, tacrine and their salts, their esters, their hydrates, their polymorphs and their isomers.
Examples of contraceptives are: desogastric, ethinyl estradiol, ethynodiol, levonorgestrel, medroxyprogesterone, mestranol, norgestimate, norethindrone, norgestrel, and their salts, esters, hydrates, polymorphs and isomers.
Agents for treating cystic fibrosis are, for example: pancrelipase, tobramycin, and their salts, esters, hydrates, polymorphs and their isomers.
Dopamine receptor agonists are, for example: amantadine, cabergoline, fenoldopam, pergolide, pramipezal, ropinirole and their salts, their esters, their hydrates, their polymorphs and their isomers.
Endometriosis treatment agents are, for example: danazol, norethindrone, and their salts, esters, hydrates, polymorphs and their isomers.
Erectile dysfunction treatment agents are, for example, sildenafil, tadalafil, vardenafil, yohimbine, and their salts, their esters, their hydrates, their polymorphs and their isomers.
Fertility treatment agents are for example: clomiphene, progesterone, and their salts, esters, hydrates, polymorphs and isomers.
Agents for treating gastrointestinal disorders are, for example:
alosetron, bisacodyl, bismuth subsalicylate, celecoxib, cimetidine, difoxin, diphenoxylate docusate, esomeprazole, famotidine, glycopyrrolate, lansoprazole, loperamide, metoclopramide, nizatidine, omeprazole, pantoprazole, rabeprazole, ranitidine, simethicone sucralfate, and their salts, esters, hydrates, polymorphs and their isomers.
Immunomodulators and immunosuppressants are for example:
azathioprine, ceftizoxime, cyclosporine, leflunomide, levamisol, mofetil, phthalidomide, ribavirin, sirolimus, tacrolimus and their salts, their esters, their hydrates, their polymorphs and their isomers.
Agents for the treatment of Alzheimer's disease are, for example: CP
118954, donepezil, galanthamine, metrifonate, revastigmine, tacrine, TAK-147, and their salts, their esters, their hydrates, their polymorphs and their isomers.
Examples of antimigraine agents are: paracetamol, dihydroergotamine, divalproex, ergotamine, propranolol, risatriptan, sumatriptan, trimetrexate, and their salts, their esters, their hydrates, their polymorphs and their isomers.

-23-Relaxants of the muscles are, for example: azapropazone, baclofen, carisoprodol, quinine derivatives, chloromezanone, chlorophenesincarbamate, chlorozoxazone, cyclobenzaprine, dantrolene, chloride dimethyltubocurarinium, fenyramidol, guaiphensin, memantine, mephenesin, meprobamate, metamisol, metaxalone, methocarbamol, orphenadrine, phenazone, phenprobamate, tetrazepam, tizanidine, tybamate and their salts, esters, hydrates, polymorphs and their isomers.
Nucleoside analogues are, for example: abacavir, aciclovir, didanosine, gamciclovir, gemcitabine, lamivudine, ribavirin, stavudine, zalcitabine, and their salts, their esters, their hydrates, their polymorphs and their isomers.
Osteoporosis treatment agents are, for example: alendronate, calcitonin, estradiol, estropipate, medroxyprogesterone, norethindrone, norgestimate, pamidronate, raloxifene, risdronate, zoledronate, and their salts, their esters, their hydrates, their polymorphs and their isomers.
Parasympathomimetics are, for example: bethanechol, bipéridine, edrophonium, glycopyrolate, hyoscyamine, pilocarpine, tacrine, yohimbine, and their salts, their esters, their hydrates, their polymorphs and their isomers.
Prostaglandins are, for example: alprostadil, epoprostenol, misoprostol, and their salts, their esters, their hydrates, their polymorphs and their isomers.
Examples of psychotherapeutic agents are acetophenazine, alpertin, alprazolam, amitriptyline, apriprazole, azaperone, batelapine, béfipiride, benperidol, benzindopyrine, bimithil, biriperone, brofoxine, bromperidol, bronipéridol, bupropion, buspirone, butaclamol, butapérazine, carphenazine, carvotroline, chlorazépine, chlordiazepoxide, chlorpromazine, chlorprothixene, cinperene, cintriamide, citalopram, clomacamperone, clonazepam, clopenthixol, clopimozide, clopipazane, cloroperone, clothiapine, clothixamide, clozapine, cyclophenazine, dapiprazole, dapoxetine, desipramine, divalproex, dipyridamole, doxepin, droperidol, duloxetine, eltoprazine, eptipirone, etazolate, fenimide, flibanserin, flucindole, flumezapine, fluoxetine, fluphenazine, fluspiperone, fluspirilene, flutroline, fluvoxamine, gepirone, gevotroline, halopemide, haloperidol, hydroxyzine hydroxynortriptyline, iloperidone, imidoline, lamotrigine, loxapine, enperone, mazapertine, mephobarbital, meprobamate, mesoridazine, mesoridazine, milnacipran, mirtazepine, meiotapine, milenperone, milipertine, molindone, nafadotride, naranol, nefazodone, neflumozide, ocaperidone, odapipam, olanzapine, oxethiazine, oxiperomide, pagoclone, paliperidone, paroxitene, penfluridol, pentiapine, perphenazine, phenelzine, pimozide pinoxepin, pipamperone, piperacetazine, pipotiazine, piquindone, piracetam, Pirlindole, pivagabine, pramipexole, prochlorperazine, promazine, quetiapine, reboxetine, remoxipride, risperidone, rimcazole, robolzotan, selegiline, seperidol, sertraline, sertindole, Seteptiline, Tetoperone, Spiperone, Sunipitrone, Tepirindole, Thioridazine, thiothixene, tiapride, tioperidone, tiospirone, topiramate, tranylcypromine, trifluoperazine, trifluperidol,

-24-triflupromazine, trimipramine, venlafaxine, ziprasidone, and their salts, their esters, their hydrates, their polymorphs and their isomers.
Sedatives, hypnotics and tranquillizers are for example:
bromazepam, buspirone, clazolam, clobazam, chlorazepate, diazepam, demoxepam, dexmedetomidine diphenyhydramine, doxylamine, enciprazine, estrazolam, hydroxyzine, ketazolam, lorazatone, lorazepam, loxapine, medazepam, meperidine, methobarbital, midazolam nabilone, nisobamate, oxazepam, pentobarbital, promethazine, propofol, triazolam zaleplon, zolpidem, and their salts, their esters, their hydrates, their polymorphs and their isomers.
Dermatological treatment agents are, for example: acitretin, alclometasone, alitretinoin, betamethasone, calciprotrin, clobetasol, clocortolone, clotrimazole, cyclosporine, desonide, difluorosone, doxepin, eflomithine, finasteride, flurandrenolide, hydrochloroquine, hydroquinone, hydroxyzine, ketoconazole, mafenide, malathion, menobenzone, neostigmine, nystatin, podophyllotoxin, povidone, tazorotène, tretinoin, and their salts, esters, hydrates, polymorphs and their isomers.
Steroids and hormones are for example: alclometasone, betamethasone, citrorelix, clobetasol, clocortolone, cortisone, danazol, desonide, desogestrel, deoximetasone, dexamethasone, diflorasone, estradiol, estrogen, estropipate, ethynylestradiol, fluocinolone, flurandrenolide, fluticasone, halobetasol, hydrocortisone leuprolide, levonorgestrel, levothyroxine, medroxyprogesterone, methylprednisolone, methyltestosterone, mometasone, norethindrone, norgestrel, oxandrolone, oxymetholone, prednicarbate, prednisolone, progesterone, stanozolol, testosterone, and their salts, their esters, their hydrates, their polymorphs and their isomers.
One can also refer to the list of PAs given in application EP 0 609 pages 4 to 8. The PA implemented belongs for example to at least one families active substances: amphetamines, analgesics, anorectics, analgesics, antidepressants, antiepileptics, anti-migraine, antiparkinsonian, antitussives, anxiolytics, barbiturates, benzodiazepines, hypnotics, laxatives, neuroleptics, opiates, psychostimulants, psychotropic drugs, sedatives, stimulants. In the case where the PA is a PA analgesic (PAa), it is preferably an opioid.
More specifically still, the PA used is chosen from the compounds following: anileridine, acetorphine, acetylalphamethylfentanyl, acetyldihydrocodeine, acetylmethadol, alfentanil, allylprodine, alphacetylmethadol, alphameprodine, alphaprodine, alphamethadol, alphamethylfentanyl, alpha-methylthio-fentanyl, alphaprodine, anileridine, butorphanol, benzethidine, benzylmorphine, beta-hydroxyfentanyl, beta-hydroxy-methyl-3-fentanyl, betacetylmethadol, betameprodine, betamethadol, betaprodine, bezitramide, buprenorphine, butyrate dioxaphetyl, clonitazene, cyclazocine, cannabis, cetobemidone, clonitazene, codeine, coca, cocaine,

-25-codoxime, dezocine, dimenoxadol, dioxaphetylbutyrate, dipipanone, desomorphine, dextromoramide, dextropropoxyphene, diampromide, diethyl-thiambutene, difenoxin, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, diphenoxylate, dipipanone, dronabinol, drotebanol, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, ecgonine, ephedrine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, etoxeridine, fentanyl, furethidine, heroin, hydrocodone, hydromorphinol, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, lofentanil, levomethorphan, levomoramide, levophenacylmorphan, levorphanol, meptazinol, meperidine, metazocine, methadone, methyldesorphine, methyldihydro-morphine, methylphenidate, methyl-3-thiofentanyl, methyl-3-fentanyl, metopon, moramide, morphine, morphine, myrophin, nabilone nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, nicocodine, nicodicodine, nicomorphine, noracymethadol, norcodeine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, phenadoxone, phenoperidine, promedol, properidine, propiram, propoxyphene, parafluorofentanyl, pentazocine, pethidine, phenampromide, phenazocine, phenomorphan, phenoperidine, pholcodine, piminodine, piritramide, proheptazine, propranolol, properidine, propiram, racemethorphan, racemoramide, racemorphane, remifentanil, sufentanil, tetrahydrocannabinol, thebacone, thebaine, thiofentanyl, tilidine, trimeperidine, tramadol, and their salts, their esters, their hydrates, their polymorphs and their pharmaceutically acceptable isomers, and mixtures thereof.
Among the anti-inflammatory PAs that may be envisaged, mention may be made of: celecoxib, ibuprofen, paracetamol, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flufuene, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofène, muroprofen, trioxaprofen, suprofen, amineoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetine, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, acid meclofenamic, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, and their salts, their esters, their hydrates, their polymorphs and their pharmaceutically acceptable isomers, and mixtures thereof.

The invention will be better explained by the following examples, given only at illustration and to understand the invention and to make stand out variants of implementation and / or implementation, as well as its different advantages. Various embodiments of the invention are illustrated as non-exemplary embodiments limiting Figures 1 to 5.

-26-FIG. 1 represents a microparticle 11 in which the PA 12 core is coated a coating 13 on which is deposited the agent D 14. The coating 13 contains the polymer A, the plasticizer B and optionally the surfactant C.
FIG. 2 represents a microparticle 21 whose PA 22 core contains a agent Dl. The heart of PA 22 is coated with a coating 23 which also contains an agent D2. Agents D1 or D2 may be the same or different from each other.
FIG. 3 represents a pellet or granule 39, for example obtained by extrusion, which contains microparticles 31 in a binder phase containing at least less an agent D. The microparticles 31 comprise reservoir microparticles and eventually uncoated microparticles of PA.
FIG. 4 represents a tablet 49 containing microparticles 41 according to the invention, for example reservoir microparticles and possibly microparticles with immediate release, in a binder 42 containing an agent D2. The tablet 49 is coated with a coating 45 containing a Dl agent. Dl agents or D2 may be the same or different from each other.
FIG. 5 represents a capsule 59 whose wall 56 is coated with a 55 coating based on a D agent. The capsule 59 contains microparticles 51 according to the invention, by example of microparticles reservoir and possibly microparticles to release immediate.
EXAMPLES
Example 1 Aciclovir Capsules - Agent D is contained in the neutral support of the microparticles Step 1 :
288 g of aciclovir and 72 g of hydroxypropyl cellulose (Klucel EF / Aqualon) are dispersed in 840 g of water. The suspension is sprayed on 240 g of gum guar (Danisco) in fluidized air bed (Glatt GPCGl).
2nd step:
1.4 g of ethylcellulose (Ethocel 20 Premium / Dow), 9.24 g of cellulose acetate butyrate (CAB 171-15 / Eastman), 1.68 g of polysorbate 80 (Tween 80 / Uniqema) and 1.68 g of triethylcitrate (Morflex) are solubilized in a mixture composed of 94%
acetone and 6% water. This solution is sprayed on 56 g of aciclovir granule (prepared in step 1).
The microparticles obtained are then placed in a gelatin capsule of size 0 (so as to have a dose of aciclovir of 150 mg per capsule).
Dissolution profiles D (%) as a function of time (h) in 900 ml of HC10,1 NOT
and in 500 ml of 0.1 N ethanoUHCl (40/60 v / v) with stirring at room temperature.
pallets to 75 rpm are given in Figure 6:

-27-It is found that the dissolution profiles in 0.1 N HC1 media and ethanol /
0.1 N HC1 (40/60 v / v) are very similar. In particular, there is no acceleration sensitive amount released in the presence of ethanol (so no dose dumping).

Example 2: Metformin capsule - agent D is contained in the coating of the capsule Step 1 :
500 g of metformin are dispersed in 2586 g of water. The solution is sprayed on 450 g of cellulose spheres (Asahi-Kasei) in a Glatt GPCGl.
2nd step:
228 g of ethylcellulose (Ethocel 20 Premium / Dow), 30 g of povidone (Plasdone K29-32 / International Specialty Products Inc.), 12 g castor oil hydrogenated polyoxyl 40 (polyoxyethyleneglyceroltrihydroxystearate: Cremophor RH 40 / ISP) and 30 g of oil ricin are solubilized in a mixture of 60% acetone and 40%
of isopropanol.
This solution is sprayed on 700 g of metformin granules prepared with step 1.
The microparticles obtained are then placed in a gelatin capsule of size 2 (so as to have a metformin dose of 150 mg per capsule).
This capsule is then film-coated with sodium carboxymethylcellulose solution (Blanose 7 LF /
Aqualon) with 20 mg of sodium carboxymethylcellulose for 60 mg of gelatin.
The dissolution profiles in 900 ml of 0.1 N HCl and in 500 ml of a mixed Ethanol / HC10.1 N (40/60 v / v) with vane agitation at 75 rpm are given in Figure 7:
It is found that the dissolution profiles in 0.1 N HC1 media and ethanol /
0.1 N HC1 (40/60 v / v) are very similar. In particular, there is no acceleration sensitive amount released in the presence of ethanol (so no dose dumping).
Example 3: aciclovir capsules - the agent D is contained in the neutral support of the microparticles and in the constituent of the capsule.
Step 1 :
288 g of aciclovir and 72 g of hydroxypropylcellulose (Klucel EF / Aqualon) are dispersed in 840 g of water. The suspension is sprayed on 240 g of gum guar (Danisco) in a Glatt GPCGl.

2nd step:
9.84 g of ethylcellulose (Ethoce120 Premium / Dow), 0.24 g of povidone (Plasdone K29 / 32 / ISP), 0.24 g of mono-oleate sorbitan (Span 80 / Uniqema) and 1.68 g of oil ricin (Garbit Huilerie) are solubilized in a mixture composed of 60%
acetone and 40%
of isopropanol. This solution is sprayed on 48 g of aciclovir granules (prepared for step 1).

-28-The microparticles obtained are then placed in a vegetarian capsule (at based of hypromellose [or HPMC]) of size 0 (so as to have a dose of aciclovir mg per capsule).
The dissolution profiles in 900 ml of 0.1 N HCl and in 500 ml of a mixed 0.1 N ethanoUHC1 (40/60 v / v) under vane agitation at 75 rpm are given in Figure 8:
It is found that the dissolution profiles in the media HC10,1 N and éthanoUHCI
0.1 N (40/60 v / v) are very similar. In particular, there is no sensitive acceleration of the amount released in the presence of ethanol (so no dumping dose).
EXAMPLE 4 Metformin Capsule Agent D is mixed with the microparticles Step 1 :
350 g of metformin, 50 g of hydroxypropylcellulose (Klucel EF / Aqualon) and100 g of sodium starch glycolate (Primojel / Avebe) are dispersed in 700 g of water and 467 g of ethanol. The solution is sprayed on 500 g of guar gum (Danisco) in a Glatt GPCGl.
2nd step:
224 g of ethylcellulose (Ethocel 20 Premium / Dow), 5.2 g of mono-sorbitan oleate (Span 80 / Uniqema) and 31.2 g of castor oil (Garbit Huilerie) are solubilized in a mixture consisting of 60% acetone and 40% isopropanol. This solution is sprayed on 390 g of metformin granulate (prepared in step 1).
Step 3:
200 g of microparticles obtained after step 2 are mixed with 65 g of mannitol (Pearlitol SD 200), 30 g hypromellose [or HPMC] (Methocel E5), 5 g of magnesium stearate and approx. 60 g of water and extruded on a 1.5 mm grid (extruder Fitzpatrick MG-55). The rods obtained are then spheronized on a plateau having a roughness of 1 mm at a speed of 1500 rpm (spheronizer of laboratory Fitzpatrick Q-230.T).
The microparticles obtained are then placed in a gelatin capsule of size 0 (so as to have a metformin dose of 80 mg per capsule).
The dissolution profiles in 900 ml of 0.1 N HCl and in 500 ml of a mixed 0.1 N ethanoUHC1 (40/60 v / v) under vane agitation at 75 rpm are given in Figure 9.
It is found that the dissolution profiles in the media HC10,1 N and éthanoUHCI
0.1 N (40/60 v / v) are very similar.
75% approx. of PA is released in both cases in 45 min, which represents the border of MR forms. To further slow down the release of the AP, the man of job

-29-may in particular increase the size of the microparticles, or increase the rate coating.

Example 5 Behavior of D Agents in Aqueous Solutions and alcoholics.
Different compounds D are introduced into a bottle containing either water (at left in the figures), a 40/60 ethanol solution v / v (bottle of right on the figures).
Figure 10 shows the appearance obtained in 15 min in the case of a substance insoluble in water and in ethanol - here sodium starch glycolate (Primojel /
Avebe), but swells more in water than in alcoholic solution.
Figure 11 shows the case of a substance soluble in water but not in the water / ethanol mixture, here guar gum (Grindsted Guar / Danisco) Figure 12 shows the appearance obtained in 30 minutes for a substance the solubility rate is higher in water than in the mixture water / ethanol, here from hypromellose [or HPMC] (Methocel E5 / Dow).

Example 6: Metformin capsule - Agent D is mixed with the microparticles Step 1 :
1700 g of metformin are solubilized in 2348 g of water. The solution is sprayed on 300 g of cellulose spheres (Cellets 90 / Pharmatrans) in a Glatt GPCGl.
2nd step :
249.6 g of ethylcellulose (Ethoce120 Premium / Dow), 19.2 g of povidone (Plasdone K29 / 32 / ISP), 12.8 g polyoxyl-40 hydrogenated castor oil (Cremophor RH

BASF) and 38.4 g of castor oil (Garbit Huilerie) are solubilized in a mixed composed of 60% acetone and 40% isopropanol. This solution is sprayed 480 g granulated metformin (prepared in step 1).
Step 3:
6 g of microparticles obtained at the end of step 2 are mixed with 0.4 boy Wut of hypromellose [or HPMC] (Methocel E4M / Colorcon), 0.2 g hydroxypropyl (Klucel HXF / Aqualon) and 0.04 g of magnesium stearate using a mixer type Rhôn wheel (Mini 80 / J. Engelsmann AG) for 30 min. The resulting mixture is then placed in a size 0 gelatin capsule (so as to have a dose of metformin about 150 mg per capsule).
Dissolution profiles in 900 ml of 0.1 N HCl, 900 ml of ethanol mixture /
0.1 N HCl (5/95 v / v) and 900 ml of 0.1 N (20/80 v / v) ethanol / HCl mixture.
a Pallet stirring at 75 rpm is given in Figure 13.
It can be seen that the dissolution profile in the 0.1 N HCl medium is similar or faster than in media containing ethanol.

Claims (24)

1. Oral pharmaceutical or dietetic form comprising microparticles of type reservoir, with modified release of at least one active principle (AP), characterized in that Resists the immediate discharge of the PA dose in the presence of alcohol. 2. Form according to claim 1, characterized in that the time of release of 50% PA, in an alcoholic solution:
- is not decreased by more than 3 times compared to the release time of 50 % of PA
measured in an aqueous medium free of alcohol;
- preferably is not decreased by more than 2 times in relation to the time of release of 50% of the PA measured in an aqueous medium free of alcohol;
- preferably is not decreased by more than 1.5 times compared to the time of release of 50% of the PA measured in an aqueous medium free of alcohol;
- is preferably similar to that measured in aqueous medium free of alcohol, according to the similarity factor f2;
- even the release time of 50% of the PA in alcoholic solution is greater than release time of 50% PA in aqueous medium free of alcohol. 3. Form according to claim 1 or 2, characterized in that it comprises at less an agent D which is a pharmaceutically acceptable compound whose rate or the ability to hydrate or to solvate is superior in aqueous medium free of alcohol alcoholic solution. 4. Form according to claim 3, characterized in that it comprises microparticles of type tank:
- whose average diameter is less than 2000 μm, more preferably between 50 and 800 μm, and even more preferably between 100 and 600 .mu.m, individually constituted by a core containing the PA and coated with a coating comprising:
.cndot. at least one insoluble polymer A in the liquids of the gastrointestinal tract intestinal;
.cndot. at least one plasticizer B;
.cndot. optionally at least one surfactant C. 5. Microparticulate form according to any one of claims 3 or 4 characterized in that the agent D is:
one of the constituents of the PA core (or microparticle not coated with PA), is :
.cndot. in the neutral support of the microparticles and / or .cndot. in the layer containing the PA, deposited on the neutral support of microparticles and / or .cndot. in the granule containing the PA; and or one of the constituents of the coating of the microparticles; and or - in mixture with the microparticles; and or one of the outer constituents of a monolithic form. 6. Form according to claim 5 characterized in that the agent D is present in the heart of PA, at 5% to 70% w / w, preferably 15% to 60% w / w of the mass total of the heart of PA. 7. Form according to claim 5, characterized in that agent D is present in the coating at a rate of 3 to 30% w / w, preferably 10% to 20% w / w of the total mass of coating. 8. Form according to claim 5 characterized in that the agent D is present in mixture with the microparticles at 2 to 30% w / w, preferably 5 to % to 25%
p / p, and more preferably still 5% to 20% w / w, of the total mass of the mixture. 9. Form according to any one of claims 3 to 8, characterized in that than Agent D is selected from the following group of products:
crosslinked carboxyalkylcelluloses: carboxymethylcelluloses crosslinked (e.g.
croscarmellose sodium), - polyalkylene oxides (eg polyethylene oxide or polypropylene oxide), - (hydroxy) (alkyl) celluloses (eg hydroxypropylcellulose, hypromellose [or HPMC]), carboxyalkylcelluloses (eg carboxymethylcellulose) and their salts, celluloses (powder or microcrystalline), potassium polacrilin, polysaccharides, for example:
.cndot. native starches (eg corn, wheat or potato) or modified (by example with sodium glycolate), .cndot. alginates and their salts such as sodium alginate, .cndot. guar gums, .cndot. carrageenans, .cndot. pullulans, .cndot. pectins, .cndot. chitosans and their derivatives, .cndot. and their mixtures, proteins, for example:

.cndot. gelatin, .cndot. albumins, .cndot. casein, .cndot. lactoglobulins, .cndot. and their mixtures, clays, such as bentonite, laponite, - and their mixtures. 10. A multimicroparticulate pharmaceutical form according to any one of Claims 3 to 9, characterized in that agent D is selected from group of products following:
hydroxyalkylcelluloses (eg hydroxypropylcellulose, hypromellose [or HPMC]), - guar gums, - carrageenans, - pullulans, - and their mixtures. Pharmaceutical form according to one of Claims 4 to 10, characterized in that the polymer A is present in the coating of the microparticles Reason to 70% to 95% w / w, preferably 75% to 95% w / w, and more preferably more 80 to 95% of the total mass of the coating without agent D, the plasticizing agent B is present in the coating of the microparticles tank at the rate of 1 to 30% w / w, preferably 2 to 25% w / w, and more preferably still, from 5 to 20%
the total mass of the coating without agent D, the surfactant C is present in the coating of the microparticles tank at the rate of 0 to 30% w / w, preferably 0 to 20% w / w, and more preferably still, from 5 to 15%
the total mass of the coating without agent D. Pharmaceutical form according to any one of claims 4 to 11, characterized in that the polymer A is selected from the group of following products:
the non-water-soluble derivatives of cellulose, - (meth) acrylic (co) polymer derivatives, - and their mixtures. Pharmaceutical form according to claim 12, characterized in that A
is selected from the following group of products: ethylcellulose, acetate butyrate cellulose, cellulose acetate, ammonio-methacrylate copolymers A and type B

(Eudragit® RS, Eudragit® RL, Eudragit® RS PO, Eudragit® PL
PO), the acid esters poly (meth) acrylics (Eudragit® NE 30D) and mixtures thereof, ethylcellulose and / or acetate cellulose being particularly preferred. Pharmaceutical form according to one of Claims 4 to 13, characterized in that the plasticizing agent B is selected from the group of products following:
glycerol and its esters, preferably in the following subgroup:
acetylated glycerides, glycerylmonostearate, glyceryltriacetate, glyceryltributyrate, phthalates, preferably in the following subgroup: dibutyl phthalate, diethylphthalate, dimethylphthalate, dioctyl phthalate, citrates, preferably in the following subgroup:
acetyltributylcitrate, acetyltriethylcitrate, tributylcitrate, triethylcitrate, the sebacates, preferably in the following subgroup: diethyl sebacate, dibutyl, - adipates, azelates - benzoates, chlorobutanol, polyethylene glycols, - vegetable oils, fumarates, preferably diethylfumarate, malates, preferably diethyl malate, oxalates, preferably diethyloxalate, succinates; preferably the dibutylsuccinate, - butyrates, esters of cetyl alcohol, malonates, preferably diethyl malonate, castor oil (the latter being particularly preferred), - and their mixtures. 15. The pharmaceutical form according to any one of claims 4 to 14, characterized in that the surfactant C is selected from the group of products following:
the alkaline or alkaline earth salts of fatty acids, sodium dodecyl sulphate and sodium docusate being preferred, polyoxyethylenated oils, preferably hydrogenated castor oil polyoxyethylene, polyoxyethylene-polyoxypropylene copolymers, polyoxyethylenesorbitan esters, polyoxyethylenated castor oil derivatives, stearates, preferably of calcium, magnesium, aluminum or zinc, polysorbates, stearyl fumarates, preferably sodium, - the glycerol behenate, - benzalkonium chloride acetyltrimethylammonium bromide, - and their mixtures. Pharmaceutical form according to Claim 4, characterized in that:
the polymer A is ethylcellulose, the plasticizing agent B is castor oil;
the surfactant C is polysorbate;
the agent D is chosen from guar gum, hypromellose [or HPMC], sodium carboxymethylcellulose, pullulan, sodium starch glycolate, and their mixtures. Pharmaceutical form according to one of Claims 3 to 16, characterized in that it contains extruded particles, the particles comprising microparticles of reservoir type, with modified release of at least one PA, and at least one agent D, agent D representing from 5 to 20% w / w of microparticles. Pharmaceutical form according to any one of claims 3 to 16, characterized in that it is in the form of a capsule, preferably one capsule gelatin base, - coated with sodium carboxymethylcellulose coating 25%
p / p of sodium carboxymethylcellulose relative to the weight of the capsules empty, - containing microparticles reservoir. Pharmaceutical form according to any one of claims 3 to 16, characterized in that it is in the form of a capsule based on a agent D, of preferably based on pullulan. 20. The pharmaceutical form according to any one of claims 3 to 16, characterized in that it is in the form of a capsule based on a agent D, of preferably based on hypromellose [or HPMC]. Pharmaceutical form according to one of Claims 3 to 19, characterized in that it contains a plurality of microparticle populations, said populations differ at least in the nature of the contained AP and / or the composition of the coating and / or the thickness of the coating and / or the location of agent D. 22. The pharmaceutical form according to claim 20 comprising at least two Types microparticles with different PA release kinetics, for example release immediate release and modified release or modified release according to kinetics of different release. 23. The pharmaceutical form according to claim 20 or 21 further comprising a mixture of several PAs, each of which is contained in microparticles having identical or different release kinetics. 24. Process for obtaining a pharmaceutical form according to any one of the preceding claims, in several steps consisting essentially of:
a) preparing hearts (uncoated microparticles) of AP by:
extrusion / spheronization of PA with possibly one or more agent (s) From where pharmaceutically acceptable excipient (s), and / or;
wet granulation of PA with possibly one or more agent (s) D or pharmaceutically acceptable excipient (s), and / or;
- compaction of AP with possibly one or more agent (s) D or excipient (s) pharmaceutically acceptable, and / or;
PA sputtering, possibly with one or more agent (s) D or excipient (s) pharmaceutically acceptable, in dispersion or in solution in a solvent aqueous or organic on a neutral support or agent D particles, and / or;
sieving of powder or PA crystals;
b) preparing microparticles reservoir of PA by:
- Spraying in a fluidized air bed of a solution or dispersion containing one or more compounds A, B and optionally one or more compounds C and / or D on the PA microparticles; the microparticles of PA may have been at pre-coated by one or more agents D; coated microparticles can eventually be coated with one or more agents D;
c) prepare the final form of the drug by:
granulation and / or extrusion / spheronization of microparticles PA with a agent D for setting in capsule or sachet; or - mixture of microparticles tank PA with possibly one or several agent (s) D
and pharmaceutically acceptable excipients for obtaining a tablet ; this The tablet may optionally be coated in a coating turbine by one or several layers containing agent D and / or pharmaceutically acceptable excipients; or - Put in capsule of the microparticles tank of PA; the capsules can eventually be embedded in a turbine or fluidised air bed by one or more agents D
and / or pharmaceutically acceptable excipients; or - Packing of the microparticles tank PA with possibly one or many agent (s) D and / or pharmaceutically acceptable excipients; or tabletting tablets containing microparticles of PA reservoirs, the tablet containing one or more agents D and capsules that may be coated by one or several agents D.